TGF-beta1 has been characterized as an important regulator of B lymphocyte growth, differentiation and immunoglobulin (Ig) class switching in vitro. In order to explore the role of TGF-beta1 on humoral immune responses in vivo, B lymphocyte function was examined in mice in which the TGF-beta1 gene was functionally disrupted [TGF- beta1(-/-)]. These animals develop multifocal infiltration of inflammatory cells in targeted organs leading to autoimmune-type lesions and death, concomitant with weaning. Symptomatic TGF-beta (- /-) mice exhibit enhanced immunostaining of IgG protein in the tissues as reflected by increased plasma Ig levels. In particular, IgM and IgG levels were increased, but mucosal IgA levels were decreased as compared to normal littermates. Polyclonal and autoreactive Ig production was also elevated. RT-PCR analyses revealed increased tissue specific mRNA expression for the cytokine IL-6 in TGF-beta1 (-/-) mice, as well as increased circulating IL-6 protein, which could exacerbate the observed changes in Ig synthesis and development of autoimmune lesions. Altered Ig production likely results in the autoimmune-like pathology in TGF-beta1-deficient mice, and reflects the importance of TGF-beta1 in B cell development, differentiation and Ig synthesis. To further explore the impact of TGF-beta1 deficiency on mucosal and other tissues, mice were infected with Schistosoma mansoni, the eggs of which lodge in liver and lung. In mice heterozygous for TGF-beta1 (+/-), pulmonary granuloma development and fibrosis were diminished compared to wild type mice, whereas in the knockouts granulomas were enlarged. Interestingly, in TGF-beta1 transgenic mice which overexpress this cytokine/growth factor, hepatic and pulmonary granulomas were also altered in degree of inflammation and matrix response. Thus, TGF-beta1 is a major influential factor in inflammation and fibrosis in mucosal and other tissue.